Prostate cancer relapsing from antiandrogen therapies can exhibit variant histology with altered lineage marker expression, suggesting lineage plasticity facilitates therapeutic resistance. Mechanisms underlying prostate cancer lineage plasticity are unknown. Our recent work published in Science uses mouse models of prostate cancer to demonstrate Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis, and antiandrogen resistance. The research program funded by R01 CA207757 proposes to identify molecular mechanisms underlying Rb1 and Trp53 function in this context and assess a novel therapeutic approach using epigenetic modulating drugs to improve responses to therapy. This R50 application proposes salary support for Meenalakshmi Chinnam, Ph.D. to support the R01 CA207757 research program. Dr. Chinnam works as a Research Associate in the laboratory of Dr. David Goodrich, unit director on this application. Dr. Chinnam has made significant contributions to Dr. Goodrich's research programs since 2004, and her work has been published in well-regarded journals. Dr. Chinnam is a skilled experimentalist with a broad background in pharmacology, molecular biology, molecular genetics, biochemistry and nutrition sciences. She has over 13 years of experience in cancer research. Relevant to this application, Dr. Chinnam has considerable experience using mouse models of prostate cancer and characterizing the histopathology of both mouse and human prostate cancer specimens. Dr. Chinnam will leverage this expertise to help generate and characterize novel mouse models proposed in R01 CA207757 to elucidate how Ezh2 or E2f1 activity influence lineage plasticity, cancer progression, and response to antiandrogens. She will also characterize human prostate cancer specimens for cross-species validation. Dr. Chinnam's contributions will be essential for successful completion of the R01 CA207757 research program.